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Comparing the effects of acute and chronic hypoxia in monocytic THP-1 cell culture, Bauer and colleagues [[5]] have described in detail the profiles of differential gene expression. TGF- 2 and hypoxia synergistically but diversely induced EMT of the HRPE cells, judging by the fluctuations in HIF-1 and target genes mRNA expression, as well as mitochondrial metabolism. A feature of the method is the ability to not only maintain in cell cultures a low level of oxygen close to the physiological norm (physioxic level), but also to gradually reduce it even further (hypoxia modeling). An important factor that largely determines the level of translation of cell proteins in response to hypoxia are post-transcriptional processes, in particular the regulation of functional dynamics of RNA. [Extracted from the article]

This review summarizes the currently known biochemical neuroadaptive mechanisms of remote ischemic conditioning. In particular, it focuses on the significance of the pro-adaptive effects of remote ischemic conditioning which allow for the prevention of the neurological and cognitive impairments associated with hippocampal dysregulation after brain damage. The neuroimmunohumoral pathway transmitting a conditioning stimulus, as well as the molecular basis of the early and delayed phases of neuroprotection, including anti-apoptotic, anti-oxidant, and anti-inflammatory components, are also outlined. Based on the close interplay between the effects of ischemia, especially those mediated by interaction of hypoxia-inducible factors (HIFs) and steroid hormones, the involvement of the hypothalamic–pituitary–adrenocortical system in remote ischemic conditioning is also discussed. [ABSTRACT FROM AUTHOR]

Hypoxia‐inducible factor (HIF‐1) as the primary factor mediating gene‐dependent cellular responses to hypoxia represents an attractive target for the therapeutic interventions. The current Editorial comments on an as yet underestimated facet of HIF‐1–related research. The activity of HIF‐1 is being regulated by the availability of its α‐subunit HIF‐1α, which undergoes quick degradation. The process of degradation is initiated by prolyl 4‐hydroxylase (PHD). PHD is an oxygen‐dependent enzyme and therefore is inactivated in hypoxia, in turn resulting in HIF‐1α stabilization, its dimerization with HIF‐1β subunit thereby producing the transcriptionally active factor. It has been suggested that pharmacological inhibition of PHD activity might give the same results. Indeed, a large body of evidence on beneficial effects of PHD inhibitors has been accumulated in multiple laboratory and clinical trials. In addition to them, a paper by Li and colleagues published in this issue of Journal of Neurochemistry also reports that inhibition of PHD by adaptaquin reduces hypoxic‐ischemic brain injury in a neonatal mouse model. When dissecting the underlying molecular mechanisms, Li and colleagues surprisingly found that the observed effects appear to be independent of HIF‐1. These findings draw attention back to the question about possible HIF‐1 effects independent of PHD inhibitors, which has been raised several years ago but has not received sufficient attention so far, and is being discussed in this Editorial. One of the possible mechanisms might be ascribed to the ferroptosis pathway affected by PHD inhibitors but this question needs further careful studies, as well as clarification of other mechanisms possibly involved. Even if they represent a prospective therapeutic strategy, the lack of current knowledge about endogenous targets of PHD inhibitors, except for PHD, calls for a careful and balanced approach toward their clinical use. [ABSTRACT FROM AUTHOR]

Abstract: The microbiome and its cross‐talk with the brain have drawn increasing attention lately, since imbalances in the gut microbiota's composition may result in pathogenic dysfunctions affecting brain functioning up to development of neurodegenerative and mental diseases. The current Editorial discusses a study by Gao and coworkers in the current issue of the Journal of Neurochemistry in which the authors use a model of antibiotic‐induced dysbiosis ‐ targeted infusion of antibiotics into the gut ‐ to assess if microbiotic metabolites exert effects on local neurotransmitter expression or contribute to the gut‐brain axis. The authors mechanistically link distal ileal infusion of antibiotics with a change in the levels of microbial metabolites that affect the expression of neurotransmitters in the brain and thereby can participate in the fine‐tuning of the hypothalamic functions, including regulation of visceral and neuroendocrine processes, stress responses, mood and anxiety. Their study thus represents an important step towards our understanding of the brain‐gut axis, with the potential to advance therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: The ADAMs (a disintegrin and metalloprotease) are a family of membrane-anchored glycoproteins capable of shedding a multitude of proteins from the cell surface. Although ADAMs are being considered as crucial modulators of physiological and pathophysiological processes, their roles in neuronal death/survival are largely unexplored. In the present study, changes in brain expression of ADAM15 and ADAM17 (TACE) have been quantitatively examined in rats in response to injurious severe hypoxia (SH) and in animals which acquired hypoxic tolerance through preconditioning to mild hypoxia prior SH. SH persistently up-regulated ADAM15 mRNA and protein levels in hippocampus and neocortex but not in thalamus or hypothalamus. This effect was not observed in the preconditioned rats tolerant to SH. In contrast, hippocampal levels of ADAM17 mRNA and neocortical levels of ADAM17 mRNA and protein were largely reduced following SH in non-preconditioned rats. Hypoxic preconditioning prevented down-regulation of the adam17 gene and considerably enhanced ADAM17 protein expression in hippocampus and neocortex in response to SH. The present findings implicate ADAM15 in the processes of neuronal hypoxic injury. On the other hand, these results also provide evidence for a pro-survival neuroprotective role of ADAM17 and its engagement in the process of preconditioning-induced hypoxic tolerance. The analysis of the protein levels of soluble and membrane-bound forms of APP in the neocortex and hippocampus of rats subjected to SH and SH with preconditioning has demonstrated that an increased ADAM17 expression in preconditioned animals 24h after hypoxia corresponded to a higher level of soluble form of APP and a reduction of the membrane bound fraction which reflects the role of ADAM17 in APP shedding. [Copyright &y& Elsevier]

Abstract: A potent neuroprotective effect of ischemic postconditioning has previously been described using cerebral artery occlusion but this is not a practical therapeutic option. The present study has been performed to determine whether postconditioning by mild episodes of hypobaric hypoxia (hypoxic postconditioning, HP) can reduce post-hypoxic brain injury in rats. Male Wistar rats were submitted to severe hypobaric hypoxia (180Torr, 3h) followed by HP (360Torr, 2h, 3 trials spaced at 24h) starting either 3h (early HP) or 24h (delayed HP) after severe hypoxia. The structural and functional brain injury was assessed by a complex of histological techniques, behavioral methods, and by testing the functions of the hypothalamic–pituitary–adrenal axis (HPA). It was found that early and delayed HP considerably attenuated post-hypoxic injury, reducing pyknosis, hyperchromatosis, and interstitial brain edema, as well as the rates of neuronal loss in hippocampus and neocortex. Delayed HP produced prominent anxiolytic effect on rat behavior, preventing development of post-hypoxic anxiety. Both modes of HP had beneficial effect on the functioning of HPA, but only delayed HP normalized completely the baseline HPA activity and its reactivity to stress. The results obtained demonstrate that postconditioning by using repetitive episodes of mild hypobaric hypoxia may provide a powerful neuroprotective procedure that can be easily adopted for clinical practice and recommended as a research tool for identification of endogenous mechanisms involved in post-ischemic neuroprotection. [Copyright &y& Elsevier]

Abstract: Effects of mild (preconditioning) and severe injurious hypobaric hypoxia (SH), as well as of their combination on hippocampal expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors and HPA axis activity have been examined in rats. As revealed by quantitative immunocytochemistry, three-trial exposure to mild hypoxia produced robust GR and MR overexpression located mainly in the neuronal nuclei in the dentate gyrus (DG) but only MR overexpression was observed in the CA1. SH induced sharp reduction of MR levels and enhanced GR expression in the CA1, suggesting that the unbalance of GR and MR observed might be at the bottom of the extensive neuronal loss seen in this area in response to SH. Contrastingly, SH in tolerant (preconditioned) rats failed to imbalance GR and MR expression in CA1 and up-regulated GR levels in DG. Radioimmunoassay of serum corticosterone showed that both preconditioning hypoxia itself and SH in tolerant rats produced moderate activation of HPA axis followed by its proper inactivation. In the non-preconditioned rats, HPA axis response to SH was impaired. Taken together, these novel results suggest that modifications of the hippocampal expression of GR and MR produced by preconditioning may contribute to the molecular and neuroendocrine mechanisms of tolerance to severe hypoxic stress. [Copyright &y& Elsevier]

Abstract: Transcription factors c-Fos and NGFI-A encoded by immediate early genes largely participate in the biochemical cascade leading to genomically driven lasting adaptation by neurons to injurious exposures including hypoxia/ischemia. Present study was designed to examine the involvement of c-Fos and NGFI-A in the development of brain hypoxic tolerance induced by mild hypoxic preconditioning. Earlier we have reported that preconditioning by repetitive mild hypobaric hypoxia (MHH) considerably increases neuronal resistance to subsequent severe injurious exposures. Herein, changes of c-Fos and NGFI-A expression in vulnerable rat brain areas (hippocampus, neocortex) in response to preconditioning MHH itself were studied using quantitative immunocytochemistry. Exposure to MHH differentially enhanced c-Fos and NGFI-A expression in neocortex and hippocampal fields 3–24h following the last MHH trial. The c-Fos up-regulation was the most pronounced in neocortex, CA1, and dentate gyrus, but it was twice lower in CA3/CA4. The up-regulation of NGFI-A in CA1, dentate gyrus and neocortex was 1.5–2-fold lower than that of c-Fos; but in CA3 and CA4 the rates of the c-Fos and NGFI-A induction were comparable. The present findings indicate that cooperative but differential activation of c-Fos and NGFI-A expression in vulnerable brain areas contribute to the development of tolerance achieved by MHH preconditioning. [Copyright &y& Elsevier]

Preconditioning using mild repetitive hypobaric hypoxia is known to increase a tolerance of brain neurons to severe hypoxia and other injurious exposures. In the present study, the effects of mild hypoxic preconditioning on the expression of transcription factors NF-κB and phosphorylated CREB (pCREB) has been studied in the neocortex of rats exposed to severe hypobaric hypoxia. As revealed by quantitative immunocytochemistry, the injurious severe hypobaric hypoxia (180 Torr, 3 h) remarkably reduced the neocortical levels of pCREB and NF-κB. The three-trial hypoxic preconditioning (360 Torr, 2 h, 3 days) induced persistent up-regulation of pCREB and NF-κB expression in the neocortex of rats 3–24 h following the severe hypoxia. In addition, the preconditioning alone which was not followed by the severe hypoxia, considerably increased neocortical pCREB and NF-κB levels. The findings suggest a role for transcription factors cAMP response element-binding protein and NF-κB in the neuroprotective mechanisms activated by the hypoxic preconditioning. [ABSTRACT FROM AUTHOR]

Summary: The preconditioning (PC) by using mild intermittent hypobaric hypoxia (PC) increases a resistance of the brain to severe hypoxia/ischemia and various stresses. Recently, potent antidepressant-like effects of PC have been described in animal models of depression. In the present study, the impact of PC on the activity and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA) impaired in depression has been studied in the model of shock-induced depression in rats. PC completely prevented depressive-like behavior (54% reduction in ambulance, 59% reduction in rearing in the open field, 654% increase of the anxiety level in the elevated plus maze), the HPA hyperactivity and the impairment of HPA feedback regulation that appeared in response to the inescapable footshock. Not affecting basal HPA activity, PC remarkably enhanced the HPA reactivity to stresses and substantially up-regulated the expression of glucocorticoid receptors in the ventral hippocampus following footshock that apparently contributes to the mechanisms responsible for the antidepressant-like action of PC. [Copyright &y& Elsevier]

Abstract: The effects of preconditioning using mild repetitive hypobaric hypoxia (360Torr for 2h each of 3 days) have been studied in the learned helplessness model of depression in rats. Male Wistar rats displayed persistent depressive symptoms (depressive-like behaviour in open field, increased anxiety levels in elevated plus maze, ahedonia, elevated plasma glucocorticoids and impaired dexamethasone test) following the exposure to unpredictable and inescapable footshock in the learned helplessness paradigm. Antidepressant treatment (ludiomil, 5mg/kg i.p.) augmented the development of the depressive state. The hypoxic preconditioning had a clear antidepressive action returning the behavioural and hormonal parameters to the control values and was equally effective in terms of our study as the antidepressant. The findings suggest hypoxic preconditioning as an effective tool for the prophylaxis of post-stress affective pathologies in humans. [Copyright &y& Elsevier]

Abstract: The patterns of expression of the Bcl-2, Bax, and Bcl-xL proteins were examined immunocytochemically in rat hippocampus and neocortex after severe hypobaric hypoxia (180 Torr for 3 h) and severe hypoxia preconditioned by intermittent mild hypoxia (360 Torr for 2 h daily, for 3 consecutive days, 24 h prior to severe hypoxia). As revealed by TUNEL assay, severe hypobaric hypoxia produced extensive apoptotic damage to the neurons of hippocampal CA1–CA4 and the neocortex but not the dentate gyrus granule cells. Remarkable posthypoxic up-regulation of Bax expression maximal at 24 h was detected in the CA1–CA4 areas of hippocampus and neocortex 3–72 h after severe hypoxia. The preconditioning to severe hypoxia protected neurons from the posthypoxic apoptotic transformations, the up-regulation of Bax expression, and resulted in persistent overexpression of Bcl-2 and Bcl-xL. We conclude that the protective action of hypoxic preconditioning is at least in part mediated by shifting of neuronal Bax/Bcl-2–Bcl-xL ratio to a favor of antiapoptotic proteins Bcl-2 and Bcl-xL. [Copyright &y& Elsevier]

Abstract: The aim of this work was to study effects of mild preconditioning hypobaric hypoxia (380Torr for 2h, repeated 3 or 6 times spaced at 24h) on brain NGFI-A immunoreactivity and passive avoidance (PA) behavior in rats exposed to severe hypoxia (160Torr for 3h). Severe hypobaric hypoxia produced extensive neuronal loss in hippocampal CA1, while the preceding hypoxic preconditioning had clear protective effect on neuronal viability of vulnerable hippocampal cells. Besides, the hypoxic preconditioning prevented impairment of acquisition and retention of PA caused by severe hypoxia. The six-trial hypobaric preconditioning was more effective in protection against PA learning deficits in severe hypoxia exposed rats than the three-trial preconditioning. The preconditioning up-regulated severe hypoxia-suppressed neocortical and hippocampal expression of NGFI-A, suggesting a possible role for NGFI-A in the neuroprotective mechanisms activated by hypoxic preconditioning. [Copyright &y& Elsevier]

The effect of preconditioning (PC) on the changes of nerve growth factor-induced gene A (NGFI-A) expression induced by severe hypobaric hypoxia was studied by in situ hybridization. A PC consisted of three trials of mild hypobaric hypoxia (360 Torr, 2 h) spaced at 24 h. The last trial was followed by severe hypoxia (SH; 180 Torr, 3 h) 24 h later. The PC hypoxia prevented the NGFI-A messenger RNA (mRNA) increase in the cortex, neostriatum, piriform cortex, amygdala and hippocampus detected 3 h after SH. The preconditioned SH caused a peak in NGFI-A mRNA expression at the 24 h time-point and thus abolished the dramatic decrease of the mRNA in vulnerable areas seen by 24 and 72 h after SH. The findings suggest a role of brain NGFI-A in the protective effect of hypoxic/ischemic PC. [Copyright &y& Elsevier]

Abstract Thioredoxins are a class of small redox-regulating proteins that have been implicated in the control of various aspects of cellular functions and seem to be one of the key regulators of signalling in the cellular responses to various stresses. Thioredoxin-2 (Trx2) is a novel mammalian thioredoxin which, in contrast to previously known cytosolic thioredoxin (Trx1), has been localized to the mitochondria. Trx2 is abundantly expressed in skeletal muscle, heart and adrenal gland, as well as in some other peripheral tissues with high metabolic activity. Using in situ hybridization and immunohistochemistry, we have studied the distribution and regulation of Trx2 expression in the rat brain. Trx2 mRNA and protein are highly expressed in the neurons in several brain regions, including the olfactory bulb, frontal cortex, hippocampus, some hypothalamic and thalamic nuclei, cerebellum and numerous brainstem nuclei. In addition, the Trx2 mRNA expression in paraventricular hypothalamic nucleus and reticular thalamic nucleus was found to be sensitive to peripheral glucocorticoids, as dexamethasone treatment caused significant elevation of Trx2 mRNA level in this area. No changes in other brain areas were observed after dexamethasone treatment. These findings implicate a significant regulatory and/or protective function of Trx2 in the nervous system. [ABSTRACT FROM AUTHOR]

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies. [ABSTRACT FROM AUTHOR]

Comparative analysis of available literature data on the pathogenetic neuroendocrine mechanisms of depression and post-traumatic stress disorder (PTSD) is provided in this review to identify their common features and differences. We discuss the multidirectional modifications of the activity of cortical and subcortical structures of the brain, levels of neurotransmitters and their receptors, and functions of the hypothalamic-pituitary-adrenocortical axis in depression and PTSD. The analysis shows that these disorders are examples of opposite failures in the system of adaptive stress response of the body to stressful psychotraumatic events. On this basis, it is concluded that the currently widespread use of similar approaches to treat these disorders is not justified, despite the significant similarity of their anxiety-depressive symptoms; development of differential therapeutic strategies is required. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia (IH) is commonly associated with pathological conditions, particularly obstructive sleep apnoea. However, IH is also increasingly used to enhance health and performance and is emerging as a potent non‐pharmacological intervention against numerous diseases. Whether IH is detrimental or beneficial for health is largely determined by the intensity, duration, number and frequency of the hypoxic exposures and by the specific responses they engender. Adaptive responses to hypoxia protect from future hypoxic or ischaemic insults, improve cellular resilience and functions, and boost mental and physical performance. The cellular and systemic mechanisms producing these benefits are highly complex, and the failure of different components can shift long‐term adaptation to maladaptation and the development of pathologies. Rather than discussing in detail the well‐characterized individual responses and adaptations to IH, we here aim to summarize and integrate hypoxia‐activated mechanisms into a holistic picture of the body's adaptive responses to hypoxia and specifically IH, and demonstrate how these mechanisms might be mobilized for their health benefits while minimizing the risks of hypoxia exposure. [ABSTRACT FROM AUTHOR]

The article presents an abstract of the study "Expression of Trap220 in Developing and Adult Rat Central Nervous System." The study will be presented at a joint meeting of the International Society for Neurochemistry and the European Society for Neurochemistry which will be organized in Berlin, Germany, from August 8-14, 1999. The study revealed the significant role played by thyroid hormone receptor-associated protein in processes of growth and differentiation of neural tissues.

Autophagy is a regulated mechanism of degradation of misfolded proteins and organelles in the cell. Neurons are highly differentiated cells with extended projections, and therefore, their functioning largely depends on the mechanisms of autophagy. For the first time in an animal model using immunohistochemistry, dot analysis, and qRT-PCR, the autophagy (macroautophagy) activity in neurons of two brain regions (hippocampus and neocortex) under normoxia and after exposure to hypoxia was studied. It was found that under normoxia, the autophagic activity was higher in the hippocampal neurons than in the neocortex of rats. In the hippocampus, the exposure of rats to hypoxia resulted in a decrease in the content of autophagy markers LC3 and p62, which was followed by activation of the autophagy-related gene expression. In the neocortex, no changes in these marker proteins were observed after the exposure to hypoxia. These data indicate that the neurons in the hippocampus and neocortex differ in the autophagy response to hypoxia, which may reflect the physiological and functional differences of the pyramidal cells of these brain regions and may to some extent account for the extreme vulnerability of the CA1 hippocampal neurons and relatively high resistance of the neocortical neurons to hypoxia. [ABSTRACT FROM AUTHOR]

Post-conditioning is exposure of an injured organism to the same harmful factors but of milder intensity which mobilizes endogenous protective mechanisms. Recently, we have developed a novel noninvasive post-conditioning (PostC) protocol involving three sequential episodes of mild hypobaric hypoxia which exerts pronounced neuroprotective action. In particular, it prevents development of pathological cascades caused by severe hypobaric hypoxia (SH) such as cellular loss, lipid peroxidation, abnormal neuroendocrine responses and behavioural deficit in experimental animals. Development of these post-hypoxic pathological effects has been associated with the delayed reduction of hypoxia-inducible factor 1 (HIF1) regulatory α-subunit levels in rat hippocampus, whereas PostC up-regulated it. The present study has been aimed at experimental examination of the hypothesis that intrinsic mechanisms underlying the neuroprotective and antioxidant effects of PostC involves HIF1-dependent stimulation of the pentose phosphate pathway (PPP). We have observed that SH leads to a decrease of glucose-6-phosphate dehydrogenase (G6PD) activity in the hippocampus and neocortex of rats as well as to a reduction in NADPH and total glutathione levels. This depletion of the antioxidant defense system together with excessive lipid peroxidation during the reoxygenation phase resulted in increased oxidative stress and massive cellular death observed after SH. In contrast, PostC led to normalization of G6PD activity, stabilization of the NADPH and total glutathione levels and thereby resulted in recovery of the cellular redox state and prevention of neuronal death. Our data suggest that stabilization of the antioxidant system via HIF1-associated PPP regulation represents an important neuroprotective mechanism enabled by PostC. [ABSTRACT FROM AUTHOR]

The present study was performed to explore the effect of severe hypobaric hypoxia (180 Torr, 3 h) and severe hypoxia followed by hypoxic postconditioning (360 Torr, 2 h, 3 episodes) on DNA fragmentation and dynamics of lipid peroxidation products in rat hippocampus. The severe hypoxia induced intense DNA fragmentation in the hippocampus. A persistent decrease of thiobarbituric acid reactive substances in the hippocampus was also detected in response to severe hypoxia while the levels of Schiff bases did not significantly change. The postconditioning prevented severe hypoxia-induced DNA fragmentation, returned the levels of thiobarbituric acid reactive substances to the baseline and decreased the levels of Schiff bases. These findings indicate that the neuroprotective effect of hypoxic postconditioning on hippocampal neurons detected as suppression of hypoxia-induced DNA fragmentation is accompanied by the changes in lipid peroxidation processes. [ABSTRACT FROM AUTHOR]

Acetylation of nucleosome histones results in relaxation of DNA and its availability for the transcriptional regulators, and is generally associated with the enhancement of gene expression. Although it is well known that activation of a variety of pro-adaptive genes represents a key event in the development of brain hypoxic/ischemic tolerance, the role of epigenetic mechanisms, in particular histone acetylation, in this process is still unexplored. The aim of the present study was to investigate changes in acetylation of histones in vulnerable brain neurons using original well-standardized model of hypobaric hypoxia and preconditioning-induced tolerance of the brain. Using quantitative immunohistochemistry and Western blot, effects of severe injurious hypobaric hypoxia (SH, 180 mm Hg, 3 h) and neuroprotective preconditioning mode (three episodes of 360 mm Hg for 2 h spaced at 24 h) on the levels of the acetylated proteins and acetylated H3 Lys24 (H3K24ac) in the neocortex and hippocampus of rats were studied. SH caused global repression of the acetylation processes in the neocortex (layers II–III, V) and hippocampus (CA1, CA3) by 3–24 h, and this effect was prevented by the preconditioning. Moreover, hypoxic preconditioning remarkably increased the acetylation of H3K24 in response to SH in the brain areas examined. The preconditioning hypoxia without subsequent SH also stimulated acetylation processes in the neocortex and hippocampus. The moderately enhanced expression of the acetylated proteins in the preconditioned rats was maintained for 24 h, whereas acetylation of H3K24 was intense but transient, peaked at 3 h. The novel data obtained in the present study indicate that large activation of the acetylation processes, in particular acetylation of histones might be essential for the development of brain hypoxic tolerance. [ABSTRACT FROM AUTHOR]

R5642 --> 545.10 --> Here we studied influences of housing environment on functional state of the body after action of ulcerogenic stressor. The effects of ulcerogenic stressor on the gastric mucosa, the hypothalamic‐pituitary‐adrenocortical (HPA) axis reactivity and glucocorticoid receptors in hippocampus, behavior and somatic pain sensitivity were compared in rats kept in enriched environment, social isolation, and standard laboratory conditions (control group). The rats aged 30 days were divided into groups and placed in standard cages 6 rats per cage (control) or 1 rats per cage (isolation) or in enriched cages 6 rats per cage (enriched environment). One month later, all rats (after 24 h fasting) were stressed by cold restraint (10˚C) for 3 h. In 3 h one half of rats in each group were decapitated to examine the gastric mucosa. Another half of rats were subjected to behavior tests (open field and elevated plus maze) and somatic pain sensitivity test (hot plate) as well as the HPA axis reactivity testing by plasma corticosterone levels induced by mild procedural stressor. Glucocorticoid receptor expression was estimated in hippocampus by immunohistochemistry. Body weight gradually increased in all groups during 1 month before exposure of stressor, however, in the isolated rats, the weight gain was greater than that in enriched and control groups. In all groups cold restraint caused the gastric erosion, the mean areas of which were not significantly differed. In behavior tests, the animals of isolated group were approximately equally divided into vulnerable (showing depressive‐like reactions in the open field) and resistant (not differed from the non‐stressed control) to ulcerogenic stress (active subgroup). All isolated rats showed a reduced level of exploratory activity in the elevated plus maze. Rats from enriched environment showed greater motor and exploratory activity, as well as lower anxiety level compared to those in isolated group. Isolated rats were most sensitive to action of pain, whereas rats kept in enriched environment were less sensitive to pain exposure. In the isolated group, the weakest corticosterone release among all groups was observed in response to mild procedural stress. Low HPA stress‐reactivity of isolated rats was combined with enhanced expression of glucocorticoid receptors in the hippocampus indicating a sensitization of the mechanisms of negative glucocorticoid feedback following prolonged social isolation. Thus, social isolation is a stressor leading to weight gain, a decrease in stress reactivity accompanied by an increase of glucocorticoid receptor expression in the hippocampus, a decrease of exploratory activity and increased of somatic pain sensitivity whereas enriched environment exerts beneficial action on functional state of the body: increases motor and exploratory activity, decreases anxiety and somatic pain sensitivity. [ABSTRACT FROM AUTHOR]

Preconditioning with repetitive mild hypobaric hypoxia is known to increase tolerance of susceptible brain neurons to severe hypoxia, whereas a single trial of mild hypoxia has been ineffective. In the present study, the effects of three-trial and one-trial hypobaric preconditioning on the expression of the protective transcription factor phosphorylated CREB (pCREB) and neurotrophin BDNF, before and after severe hypobaric hypoxia, have been comparatively studied in the neocortex of rats. As revealed by quantitative immunocytochemistry, the severe hypobaric hypoxia (180Torr, 3h) substantially down-regulated the levels of pCREB and BDNF in cortical neurons assessed 24h after the treatment. One trial of mild hypoxia (360Torr, 2h) also reduced by half the number of BDNF-expressing cells, but had no effect on pCREB expression in the neocortex. In contrast, the exposure to three trials of mild hypoxia at 24h intervals considerably up-regulated pCREB and BDNF levels in the neocortex of rats. Only preconditioning by three trials of mild hypoxia (360Torr, 2h, 24h intervals), but not a single trial preconditioning, was neuroprotective significantly enhancing the pCREB and BDNF neuronal expression in response to severe hypoxic challenge. The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial mild hypoxic preconditioning is apparently associated with activation of CREB and BDNF expression. [ABSTRACT FROM AUTHOR]

Abstract: Severe hypoxia results in functional and structural injury of the brain. A preconditioning with repetitive episodes of mild hypoxia considerably ameliorates neuronal resistance to subsequent severe hypoxia. Activation of endogenous antioxidants including Cu, Zn-depending superoxide dismutase (Cu, Zn-SOD) (EC.1.15.1.1) is one of the main cell defense mechanisms against oxidative stress induced by hypoxia. Alterations of expression and enzyme activity of Cu, Zn-SOD 3 and 24h after severe hypobaric hypoxia in forebrain structures of preconditioned and non-preconditioned rats were investigated. We found that hypoxia without preconditioning suppressed the Cu, Zn-SOD enzyme activity at 3h time-point but preconditioning essentially modified the reaction to severe hypoxia by increasing the expression and activity of Cu, Zn-SOD during early stages of reoxygenation crucial for apoptosis initiation. [Copyright &y& Elsevier]

Induction of endogenous antioxidants is one of the key molecular mechanisms of cell resistance to hypoxia/ischemia. The effect of severe hypoxia on the expression of cytosolic antioxidant thioredoxin-1 (Trx) in hippocampus and neocortex was studied in preconditioned and non-preconditioned rats. The preconditioning consisted of three trials of mild hypobaric hypoxia (360Torr, 2h) spaced at 24h. Twenty-four hours after the last trial rats were subjected to severe hypobaric hypoxia (180Torr, 3h). Trx expression was studied by immunocytochemistry. In hippocampus severe hypobaric hypoxia rapidly induced Trx expression, which remained elevated still at 24h. In neocortex the enhanced expression appeared only at 24h. The preconditioning significantly augmented severe hypoxia-induced Trx-immunoreactivity at 3h but not at 24h. These findings point out that Trx contributes to mechanisms of brain tolerance to hypobaric hypoxia, especially in early periods after the exposure. [Copyright &y& Elsevier]

S100 calcium-binding protein A8 (S100A8), a danger-associated molecular pattern, has emerged as an important mediator of the pro-inflammatory response. Some S100 proteins play a prominent role in neuroinflammatory disorders and increase the secretion of pro-inflammatory cytokines in microglial cells. The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action. In this study, we reported that the S100A8 protein expression was increased in mouse neuronal and microglial cells when exposed to hypoxia, and induced neuroinflammation and neuronal apoptosis. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia. Also, phosphorylation of ERK via the TLR4 receptor induced the priming of the NLRP3 inflammasome. The changes in Cyclooxygenase-2 (COX-2) expression, a well-known inflammatory activator, were regulated by the S100A8 expression in microglial cells. Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia. These results suggested that S100A8 may be an important molecule for bidirectional microglia-neuron communication and a new therapeutic target for neurological disorders caused by microglial inflammation during hypoxia. [ABSTRACT FROM AUTHOR]